P1499: GENETIC FACTORS OF IRON OVERLOAD IN HEREDITARY SPHEROCYTOSIS
Authors: Lucie Donaty, Muriel Giansily Blaizot, Severine Cunat, Vincent Azoury, Corinne Favier, Vanessa Debant, Fabienne Danton, Robert Navarro, Perrine Mahé, Patricia Aguilar Martinez
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Hereditary spherocytosis (HS) is the most common inherited chronic hemolysis in northern European populations. Although poorly documented compared to other red blood cell membrane disorders, non-transfusional iron overload (IO) has been described in patients with HS. However, the underlying pathophysiological mechanisms are not fully understood. Aims: We looked for intrinsic (related to the HS genotype) or additional genetic factors of IO that could explain the development of IO in a cohort of HS patients. Methods: We retrospectively listed patients with HS who consulted at Montpellier University Hospital between 1996 and 2022. We collected clinical, biological and medical management data, with a focus on those related to iron homeostasis. High-throughput sequencing using an Illumina MiSeq© instrument and the Agilent SureSelect© technology (NGS) was performed in patients with proven IO (LIC values by MRI ≥ 90 μmol/g). The panel consisted of 50 genes, including those responsible for HS and genes involved in rare forms of hereditary IO and other causes of constitutional hemolytic anemia. Results: A total of 141 patients with HS were collected, 45 of whom were older than 18 years. Chronic hyperferritinemia was found in 29 adults patients (64%). Of these, 14 including 8 with proven hepatic IO had DNA sequencing by NGS. IO was not directly related to the genes or variants responsible for HS, nor to the HFE:p.(Cys282Tyr) variant, responsible for common form of hereditary haemochromatosis (HH). On the other hand, genetic factors that may contribute to hepatic OI were identified in 4 of the 8 iron-overloaded patients and in a young adult with elevated ferritin levels of 351 µg/L but a LIC measured by MRI at 45µmole/g (N<36). Two patients were heterozygous for a likely pathogenic variant in genes responsible for hereditary IO: HJV:c.863G>A (or p.Arg288Gln) and SLC40A1:c.744G>T (or p.(Gln248His)) also known as the Bantu siderosis. The latter was found in the young patient who had no significant IO on MRI. Three other patients were heterozygous for variants in the PKLR and ABCG5 genes, which encode pyruvate kinase and a transporter of the superfamily of ATP-binding cassette (ABC) respectively. One patient carried the PKLR:c.1010G>A (or p.(Arg337Gln)) pathogenic variant, another the rare PKLR:c.1516G>A or (p.(Val506Ile)) variant of uncertain significance, and the last the splice variant ABCG5:c.1762 + 1G>T. Abnormalities in these genes could increase hemolysis in HS patients and lead to the development of IO. Finally, 3 common polymorphisms on the HFE, KIF23 and GLRX5 genes were found more frequently in this group of HS patients with hyperferritinemia compared to the general population. Summary/Conclusion: In this series, the search for a genetic explanation for the development of IO in some patients with HS did not show an association with the genotype leading to HS, nor the association of common genetic variants causing HH. However, we found genetic variants involved in IO and in red cell enzymopathies in 4 out of 8 patients with significant IO. These results encourage larger studies to better characterize the clinical heterogeneity observed in these patients. Keywords: Ferritin, Iron overload, Hereditary spherocytosis, Genetic modifiers